Laparotomy prevents lethal endotoxemia in a murine sequential insult modelby an IL-10-dependent mechanism

Multiple organ dysfunction and death are common sequelae after mesenteric i schemia-reperfusion injury as seen with mesenteric revascularization and th oracoabdominal aortic aneurysm repair. A second insult such as bacterial pn eumonia occurring subsequent to the ischemia-reperfusion injury may contrib ute to these untoward effects. We hypothesized the sequential visceral/lowe r torso ischemia-reperfusion and endotoxemia in a murine model would increa se the magnitude of the proinflammatory cytokine response and decrease surv ival. C57BL/6 mice underwent 20 min of supraceliac occlusion (IR), sham lap arotomy (LAP), or no initial insult (CTRL) followed by intraperitoneal inje ction of a lethal dose of endotoxin (LPS [lipopolysaccharide 50 mg/kg] or s aline vehicle at 24 h. Serum cytokine levels were measured by enzyme-linked immunosorbent assay (IL-10, IL-6) or WEHI bioassay [tumor necrosis factor (TNF)], and survival was determined at 5 days. The role of IL-10 on the TNF response and survival was examined in a subset of mice given mouse anti IL -10 IgM (25 mg/kg intraperitoneally) 2 h prior to the initial insult. Survi val after LPS was significantly different (P < 0.05) among the treatment gr oups (IR, 64%; LAP, 55%; CTRL, 11%) and appeared to trend directly with the magnitude of the initial operation. The serum IL-10 levels in the IR and L AP groups were significantly increased 4 h after the initial insult and rem ained elevated at 24 h. Peak serum TNF levels after LPS were significantly lower in the IR and LAP groups. Administration of anti IL-10 IgM resulted i n uniform mortality and a significant increase in the peak TNF levels after LPS administration for all initial treatment groups. Endogenous production of IL-10 following [aparotomy downregulates the TNF response and improves survival after endotoxemia.